1. Field of the Invention
The present invention relates to compositions and methods for treating neoplasms in mammals, particularly human. More particularly, combinations for intravenous administration of tumor agents comprising targeting compound, anticancer drugs and agents that enhance the inflammatory response are provided, an intravenous route of the only effective route of administration for treatment. Also provided are methods for treating neoplasms by administration of the combinations.
2. Description of the Related Art
A number of approaches, including surgery, chemotherapy and radiation, to cancer therapy have been used. Surgery is a traditional approach in which all or part of a tumor is removed from the body. Surgery generally is only effective for treating the earlier stages of cancer. However, for more than 50% of cancer patients by the time they are diagnosed, they are no longer candidates for effective surgical treatment. Surgical procedures may increase tumor metastases through blood circulation during of the surgery procedure. Most of cancer patients do not die from the cancer at the time of diagnosis or surgery, but rather die from the metastasis and the recurrence of the cancer.
Other therapies are also often ineffective. Radiation therapy is only effective for local cancer therapy at early and middle stages of cancer, and is not effective for the late stages of cancer with metastasis. Chemotherapy can be an effective method, which is commonly used, but there are severe side effects, e.g., vomiting, low white blood cells (WBC), loss of hair, loss of weight and other toxic effects. Because of the extremely toxic side effects, many cancer patients cannot successfully finish a complete chemotherapy regimen. A considerable number of cancer patients die from the chemotherapy due to poor tolerance to the toxic side effects of chemotherapy. The extreme side effects of anticancer drugs are caused by the poor target specificity of such drugs. The drugs reach most normal organs of patients as well as intended target tumors through circulation. Meanwhile, the poor target specificity wherein only a small fraction of the drugs is correctly targeted and a majority of drugs acts on non-targeted tissues causes side effects also decreases the efficacy of chemotherapy because. The efficacy of chemotherapy is further decreased by poor retention of the anti-cancer drugs within the target tumors. Accordingly, enhancing the target specificity of drugs is one solution to increase the retention behavior of drugs within tumors and the specified local tumor killing.
Immunotherapy, including the use of cancer vaccines, such as autologous vaccines, is effective for cancer patients with tumor burdens of less than 108 tumor cells. Immunotherapy is often used as an adjunctive therapy in combination with other therapies such as surgery, radiation therapy and chemotherapy to clean out any remaining tumor cells from the body. Immunotherapy and the use of tumor vaccines have not proven effective against a tumor burden greater than 5×109 to 1011 tumor cells, which is typical in a patient with small, symptomatic metastases. In addition, autologous tumor vaccination involves complicated procedures and requires a tumor specimen be processed for each patient to be treated, thus it is not capable to fulfill the needs of patients.
At present, there is no effective treatment for patients with late stage tumors. Since earlier stage tumors are not easily detectable, many patients who are diagnosed with cancer are at the later stages of cancer with the tumor burden greater than 5×109 to 1011 tumor cells, or the tumor has already metastasized into other tissues. For these patients, traditional cancer therapies such as surgery, radiation therapy and chemotherapy may no longer be effective and/or suitable.
A series of compounds have been found laboratorially and clinically to have the specificity of tumor targeting. Some of them have been utilized in clinical tumor imaging and therapy. However, the targeting drugs used for treatments are chosen mostly from radioisotopes, and the effect is still limited to pain killing, which is not capable to achieve partial or complete alleviation. Currently treatments of tumors still emphasize comprehensive therapy, especially by combination of immunotherapy and chemotherapy, which have been proven theoretically to be the best partners in clinical practices, even certain immunological effects achieved by chemotherapy.
Despite some progress of cancer therapy, there are few, if any, effective treatments. Due to the severity and breadth of late stage cancer towards life, there is a great clinical need for effective treatments of such diseases or disorders. The desired cancer therapy is one that treats primary tumors by targeting carrier delivery of drugs and meanwhile stimulates the autologous immunological competence in human body to eradicate systemic small tumors at multiple sites in the body, and that discriminates specifically between neoplastic and non-neoplastic cells, thus achieving the treatment and prevention of the tumor metastasis.
Accordingly, it is an object of the present invention to provide a method for such cancer therapy. In particular, it is an object of the present invention to provide a carrier targeting therapy which treats primary tumors or systemic tumors and meanwhile stimulates the autologous immunological competence within human body to eradicate systemic small tumors at multiple sites in the body, and which discriminates specifically between neoplastic and non-neoplastic cells, thus achieving the treatment and prevention of the tumor metastasis.
The present invention differs from the previous invention of the Applicant (Chinese Patent Application No. 01806830.8, Publication No. CN1431909A, published on Jul. 23, 2003.):
1. The present invention mainly relates to a method of tumor therapy by intravenous administration, while the previous invention relates to a method of tumor therapy by intratumoral administrations;
2. The present invention relates to an integration of carrier drug(s) and adjuvant(s), which may be a conjugate or in other joined forms, while the previous invention is directed to a composition of some compounds, which may not be a conjugate;
3. The conjugate of the invention, wherein the carrier still functions to deliver drugs to targeted sites (tumors or organs where tumors locate), and the drug(s) and adjuvant(s) function independently to achieve the purpose of treatment, while the previous invention only relates to a composition of some compounds without carrying or targeting effects, wherein such combination only acts within local tumors;
4. The reduce agent of the present invention functions only when the conjugate is formed, and is not involved in the action of tumor therapy, while the reduce agent of the previous invention functions during the formation of sustained released drugs within tumors, and also functions to directly kill tumor cells;
5. The present invention relates to a method of systemic therapy, which can directly treat tumors located in more than one sites, while the previous invention only relates to a method of local therapy, which can only treat local tumors;
6. The present invention is consistent with the previous one in that the inflammatory response and immunological response of the treated tumors are the same, which may results in antibodies against tumor and lymphocytes with cytotoxicity that function to kill and wound tumors.